CHEMISTRY AND BIOLOGY OF PLATINUM ANTICANCER DRUGS

铂类抗癌药物的化学和生物学

• 批准号: 7955152
• 负责人: Stephen J. Lippard
• 金额: $ 0.22万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955152
• 关键词: Antineoplastic Agents; Base Pairing; Biology; Chemistry; Cisplatin; Colorectal Cancer; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Adducts; DNA Structure; Data; Funding; Genetic Transcription; Grant; Institution; Left; Lesion; Major Groove; Modeling; Molecular Conformation; Molecular Mechanisms of Action; Mus; Platinum; Platinum Compounds; Proteins; Research; Research Personnel; Resources; Side; Site; Source; Structural Models; Structure-Activity Relationship; United States National Institutes of Health; Work; X ray diffraction analysis; X-Ray Diffraction; adduct; antitumor agent; crosslink; cytotoxicity; in vivo; interest; pyridine; repaired; structural biology; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The platinum compound cis-[Pt(NH3)2(pyridine)Cl]Cl has previously demonstrated potent cytotoxicity in a screen against in vivo murine tumor models. This result is of particular interest because this compound forms only monofunctional adducts with DNA, and thus does not follow the classic structure-activity relationship for platinum anti-tumor agents that requires two leaving groups to be present in a cis conformation. Recent data has shown this compound may be recognized by cellular repair proteins and block transcription in a manner that is unique to monofunctional platinum compounds, but similar to cisplatin and other bifunctional platinum compounds. It is therefore desirable to obtain a detailed structural model of this platinum-DNA adduct, which may help to explain the unexpected activity of the complex. We have recently crystallized a DNA dodecamer duplex containing a single {Pt(NH3)2(pyridine)}-dG adduct, and collected X-ray diffraction data to 2.17 ¿. The global structure of the DNA is quite different from that of DNA containing a platinum intrastrand d(GpG) cross-link. The latter platinated duplex is bent by ~40¿ towards the major groove at the site of the cross-link, yet the monofunctional platinumdG lesion causes no significant distortion of the double helix. Like the cisplatin intrastrand cross-link, however, the monofunctional adduct creates a distorted base pair step to the 5' side of the platinum site that may be correlated to antitumor activity. These data allow us to reevaluate the structure-activity relationship of platinum anticancer agents to include monofunctional, "non-classical" platinum compounds, and to use this evidence to work towards elucidating the molecular mechanism of action of a unique platinum complex that may be able to be used in treatment of colorectal cancer.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 铂化合物cis-[Pt（NH3）2（吡啶）Cl]Cl先前已在针对体内鼠肿瘤模型的筛选中证明了有效的细胞毒性。该结果是特别令人感兴趣的，因为该化合物仅与DNA形成单官能加合物，因此不遵循铂抗肿瘤剂的经典结构-活性关系，其需要两个离去基团以顺式构象存在。 最近的数据表明，这种化合物可以被细胞修复蛋白识别，并以单功能铂化合物特有的方式阻断转录，但与顺铂和其他双功能铂化合物相似。 因此，希望获得这种铂-DNA加合物的详细结构模型，这可能有助于解释复合物的意外活性。 我们最近结晶的DNA十二聚体双链体含有一个单一的{Pt（NH 3）2（吡啶）}-dG加合物，并收集X射线衍射数据到2.17。DNA的整体结构与含有铂链内d（GpG）交联的DNA完全不同。后一种含铂双链体在交联位点处向大沟弯曲约40 <$s，而单官能铂双链体在交联位点处向大沟弯曲约40 <$s。dG损伤不引起双螺旋的显著变形。然而，与顺铂链内交联一样，单官能加合物在铂位点的5'侧产生扭曲的碱基对台阶，这可能与抗肿瘤活性相关。这些数据使我们能够重新评估铂类抗癌药物的结构-活性关系，包括单功能的“非经典”铂化合物，并利用这些证据来阐明一种独特的铂络合物的分子作用机制，这种铂络合物可能用于治疗结直肠癌。